Oral,nasal and labial compositions containing menthyl keto esters

ABSTRACT

COMPOSITIONS FOR APPLICATION TO THE ORAL AND NASAL AREAS OF THE BODY ARE DISCLOSED WHICH CONTAIN ALPHA, BETA, GAMMA, DELTA, EPSILON, ZETA ANDETA KETO ESTERS OF MENTHOL. THESE COMPOSITIONS IMPART A LONG-LASTING COOLING SENSATION TO TISSUES OF THE LIPS AND THE MUCOUS MEMBRANES OF THE ORAL CAVITY AND NASAL PASSAGES.

3,793,463 ORAL, NASAL AND LABIAL COMPOSITIONS CONTAINING MENTHYL KETOESTERS Alfred H. Moeller, Tenafly, Michel Demont, River Vale, and AlbertG. Nickstadt, Ridgewood, N.J., assignors to Nickstadt-Moeller, Inc.,Ridgefield, NJ.

N Drawing. Original application May 14, 1969, Ser. No. 824,664. Dividedand this application Nov. 26, 1971, Ser. No. 202,689

Int. Cl. A61k 27/00 US. Cl. 424-308 5 Claims ABSTRACT OF THE DISCLOSURECompositions for application to the oral and nasal areas of the body aredisclosed which contain alpha, beta, gamma, delta, epsilon, zeta and etaketo esters of menthol. These compositions impart a long-lasting coolingsensation to tissues of the lips and the mucous membranes of the oralcavity and nasal passages.

This is a division of application Ser. No. 824,664 filed May 14, 1969,now Pat. No. 3,644,613.

This invention relates to improved compositions for use in the oral andnasal areas of the human body. More particularly, this invention relatesto compositions which, in their intended mode of usage, come intocontact with the nasal passages, the oral cavity, throat and/ or thelips, and which contain certain keto esters of menthol to impart acooling sensation to the tissues of these areas. |Such compositionsinclude, but are not limited to nasal drops, sprays and inhalants, coughdrops, cough syrups, soothing agents for the throat, lipsticks, lippomades, mouthwashes, mouthsprays and dentifrices.

The cooling sensation evoked by various aromatic substances is generallyconsidered pleasant and desirable in and around the oral and nasal areasof the body. Consequently, many products which come into contact withthese areas contain such cooling ingredients. The most commonly usedingredient for imparting this sensation has been menthol. However, thereare certain disadvantages in using menthol for this purpose. Firstly,the presence of menthol in a product severely limits the formulatorschoice of odor and/ or flavoring for the product. This is becausementhol has a distinctive minty odor and flavor and an immediate andrelatively harsh impact on the mucous membranes of the mouth, nose andthroat and on the sensitive areas of chapped lips. Secondly, the coolingsensation of menthol while intense on first application, wastes awayrapidly with time. In an endeavor to extend the life of the coolingsensation, the only recourse in the past has been to increase the levelof menthol in the product. The relatively large quantity of mentholrequired to prolong the cooling sensation significantly can irritate themucous membranes and cause a burning sensation. Because the sensitivityof the tactile senses differs so much from person to person, a suitablebalance of the two effects has been diificult to attain.

The utilization of menthyl keto esters as additives for smoking tobaccoproducts is described by Jarboe US. Pat. 3,136,319, issued June 9, 1964.The sole basis for the inclusion of such materials into smoking tobaccoproducts is for the desired benefit whereby the harshness associatedwith the smoke of a tobacco product is substantially eliminated.Moreover, it is stated that the additive or its desirable mentholcomponent is released into the smoke stream on smoking the tobaccoproduct at a satisfactorily regulated rate.

It is clear from the teaching of the aforementioned Iarboe patient thatthe desired result it attained only when United States Patent 0 thesecompounds are subjected to the high temperatures of burning tobacco. Itis quite apparent therefore that the long-lasting cooling effectdisclosed herein which derives from direct contact with the tissues ofthe mucous membranes of the oral cavity and throat and nasal passages atambient temperatures is not suggested to one skilled in the art.

It is the object of this invention to provide improved organolepticcompositions for application to the oral, throat and nasal areas of thehuman body.

It is a further object of this invention to provide compositions whichimpart a long-lasting cooling effect upon contact with the tissues ofthe nasal, oral and throat areas.

It is still a further object of this invention to provide compositionswhich impart a long-lasting cooling efiect without a strong minty odorand taste or irritating effect.

It has been found that these objectives can be achieved by oral, nasalor labial compositions as hereinafter defined comprising (1) from about0.01% to about 2.0% by weight of a menthyl keto ester of the formula:

CHa- I OHa H wherein R is an organic radical such as alkyl (e.g. methyl,ethyl, propyl or butyl), aryl (e.g., phenyl or naphthyl) or aralkyl,(e.g., benzyl), and n is an integer from 0 to 6; and (2) a carriersuitable for use in the oral cavity, e.g. an oily solvent or emulsionsuitable for use on mucous membranes, or a solid wax base. The mentholfrom which the above-described esters are derived can be l-menthol andits isomers. Examples of such preferred esters of menthol are menthylpyruvate, menthyl acetoacetate, menthyl levulinate, menthyl gamma acetylbutyrate and menthyl benzoylacetate. A procedure for preparing menthylketo esters is described in Journal of the American Chemical Society,vol. 73, pp. 4195-7. Other esters of methanol which can be employedherein include the following: menthyl u-ketobutyrate, menthyla-ketovalorate, menthyl fl-ketovalerate, menthyl phenylpyruvate, menthyl'y-ketocaproate, menthyl delta valerylvalerate, menthyl epsilonnaphthoyl-caproate and menthyl zeta phenylacetyl enanthylate.

These compositions produce a persistent cooling effect when applied tothe lips and membranes of the throat, oral and nasal cavities. Incontrast to compositions containing menthol, this long-lasting coolingsensation on the lips and throat, oral and nasal membranes is achievedwithout irritation of these sensitive areas. Moreover, menthyl ketoesters do not have a strong minty odor or taste. Therefore, unlikementhol, they can be used as fiavorant additives in compositions inwhich a non-minty odor or taste is desired.

The menthyl keto esters can be used at levels between 0.01% and 2.0% andpreferably at levels between 0.05% and 1.5% by weight in thecompositions of this invention. Less than 0.01% will give practically nocooling eflect, while more than 2.0% is likely to give an unpleasanttaste. Within the aforementioned range, the level of menthyl keto esterchosen for use in a given product will depend on the intensity ofcooling eifect desired and on the mode of usage of the product. Forexample, a single usage portion of undiluted mouthwash is about 15 gramscompared to a single usage portion of about one gram for a toothpaste.To impart the same cooling effect, therefore,

it is necessary to use much more menthyl keto ester in a toothpaste thanin a mouthwash.

Although it is to be understood that the flavor portions of thecompositions to be described hereinafter can consist entirely of thementhyl keto esters, these esters are actually relatively flavorless andtherefore it is preferable to include conventional flavoring substancesin the flavoring portions of said compositions.

The compositions of this invention can be classified as oral, nasal orlabial. The term oral compositions, as used herein, refers to allproducts which, in the ordinary course of usage come into contact withthe membranes of the oral cavity and throat, that is, products which areapplied to, or ingested through the oral cavity. Such products includedentifrices, mouthwashes and mouthsprays, chewing gums, confections,including medicated confections such as cough drops, cough syrups andlozenges and coatings encapsulating such products; and cough syrups andgum soothing agents.

Dentifrices typically contain an abrasive polishing material, sudsingagents, flavoring and sweetening agents. Toothpastes usuallyadditionally contain humectants and binders.

Any abrasive polishing material which does not excessively abrade dentincan be used in dentifrice compositions. These include, for example,calcium carbonate, dicalcium orthophosphate dihydrate, calciumpyrophosphate, calcium polymetaphosphate, insoluble sodiumpolymetaphosphate and resinous abrasive materials such as particulatecondensation products of urea and formaldehyde and others disclosed byCooley et al. in US. Pat. 3,070,- 510, granted Dec. 25, 1962.

The total amount of abrasive materials in the dentifrice embodiments ofthis invention can range from 0.5% to 95% by weight of the dentifrice.(All percentages specified hereinafter refer to weight percent of thetotal composition unless otherwise specified.) Preferably, toothpastescontain from 20% to 60%, and toothpowders contain from 6% to 95%.

Dentifrices usually contain sudsing agents. Suitable sudsing agents foruse in the dentifrices of this invention are those which yieldsubstantial levels of foam and which are otherwise acceptable for use inthe oral cavity. Examples of suitable sudsing agents include thewater-soluble salts of alkyl sulfate having from 10 to 18 carbon atoms,e.g., sodium coconut monoglyceride sulfonate; water-soluble salts offatty acid amides of taurine, e.g., sodium N-methyl-N-palmitoyl tauride;Water-soluble salts of fatty acid esters of isethionic acid, e.g., thecoconut acid ester of sodium isethionate; and substantially saturatedaliphatic acyl amides of saturated aliphatic monoaminocarboxylic acidhaving 2 to 6 carbon atoms and in which the acyl radical contains 12 to16 carbon atoms, e.g., sodium N-lauroyl sarcosinate. Mixtures of two ormore sudsing agents can also be used.

The sudsing agent can be employed at levels ranging from about 0.5% to5.0%.

Suitable flavoring agents for use in the dentifrices herein include, forexample, Wintergreen oil (methyl salicylate), oil of peppermint, oil ofsassafras (synthetic), and oil of anise. Flavoring agents are present ata level of from 0.01% to 2.0%. Sweetening agents include, for example,saccharin, dextrose, levulose, and sodium cyclomate.

In toothpastes it is desirable to employ thickening agents such ashydroxyethylcellulose and water-soluble salts of cellulose ethers,including sodium carboxymethyl cellulose and sodiumcarboxymethylhydroxyethyl cellulose; or natural gums, including gumkaraya, gum arabic and gum tragacanth. Also, colloidal magnesiumaluminum silicate or finely divided silica can be used as part of thethickening agent to improve the texture of the product. Thickeningagents in an amount of from 0.1% to 5.0% can be used.

It is also desirable to include some humectant or viscosity modifyingmaterial in toothpastes. Suitable materials for these purposes includeglycerine, sorbitol, and other edible polyhydric alcohols or mixturesthereof. These materials can comprise up to 40% of the toopthpastecomposition. In addition to the aforementioned typical components of atoothpaste, water is normally present in toothpastes at levels up to 50%Mouthwashes generally comprise a water/ ethyl alcohol solution and about0.01% to about 2.0% of flavoring materials such as those mentioned abovefor dentrifrices. The alcohol provides an antibacterial effect and alsosolubilizes the flavoring materials. Optionally, mouthwashes alsocontain additional antibacterial agents such as cetyl trimethylammoniumchloride, sudsing and sweetening agents such as those mentioned abovefor dentifrices, and humectants such as glycerine and sorbitol whichgive a moist feel in the mouth.

Typically, mouthwashes contain 10% to 60% ethyl alcohol, 30% to water,5% to 20% glycerine or other humectant, 0.1% to 2% sudsing agent, 0.05%to 0.5% sweetening agent such as saccharin and 0.05 to 0.3% flavoringagent.

These aforesaid mouthwash compositions can also be administered invaporizer or aerosol forms. When administered in aerosol form, commonlyavailable propellants such as hydrocarbons and fluoro-halogenderivatives, for example, dichlorodifluoromethane andtetrafluoridichloroethane are used.

Chewing gum comprises a gum base and flavoring materials such as thosementioned above for dentifrices. The flavoring materials are present ata level of 0.01% to about 2.0% of the final chewing gum composition. Thegum base is a chewable plastic gum material such as natural rubber,chicle, polyvinyl acetate, ester gum, coumarone resin, and paraffin wax.The gum base is typically made from a mixture of two or more plastic gummaterials to achieve a preferred degree of plasticity for chewing.Optionally, corn syrup is added as a softener and binder for the chewinggum and sugar is optionally added as a filler and sweetener. Typicalchewing gum compositions comprise 20% to 30% gum base, 15% to 20% cornsyrup, 50% to 65% sugar and 0.05% to 1.5% flavoring materials.

Confections comprise a sugar base and one or more flavoring materials.The flavoring materials are present at levels between 0.01% and 2.0%.Optionally, confections can contain various other materials in order toprovide confectionery compositions having a wide variety of physcalcharacteristics. Examples of these optional materials include water,syrups such as corn syrup, starches such as cornstarch, vegetable fatsand oils such as cocoa butter and coconut oil, and binders such as gumacacia.

A typical confection is a hard candy comprised of a hard candy base and0.05% to 1.5% flavor. The hard candy base is a solidified solution ofamorphous sugar which is generally formed from a sugar solution whichhas been cooked at high temperature so as to remove nearly all of themoisture. The flavoring materials are added before the moisture isremoved. The flavoring materials mentioned hereinbefore for dentifricesare also exemplary of those suitable for use in confections. Forconfections such as cough drops, cough syrups and throat lozengesmedicaments such as antibacterials (e.g. cetyl pyridinium chloride) orantitussive (e.g. diphenhydramine hydrochloride) are often included inthe composition.

Those oral composition ingredients other thanmedicaments and the ketoesters of menthol recited in the foregoing disclosure are exemplary ofcarriers suitable for use in the oral cavity. I

The term nasal compositions, as used herein, refers to products which,in the ordinary course of usage, are applied to the nasal passage. Suchcompositions can comprise an oil-in-wateror water-in-oil emulsion or anoily solvent base suitable for use on the mucous membranes such as lightmineral oil, vegetable oils, and fatty acid esters, and one or morearomatic chemicals which are soluble in the base such as camphor,thymol, pine oil, eucalyptol and menthol. These aromatic chemicals arepresent in the oily solvent base or in the emulsion at levels between0.01% and 2.0%. When comprised of these basic components, thecompositions are liquid including liquids ofivarying viscosities, andare applied to the nasal cavity in the form of drops, sprays or jellies.

If it is desired toapply them in the form of a solid, such as nosestick, one or more waxes such as White wax .or spermaceti is included inthe composition at levels from about 20% to about 80%. This gives a softwaxy composition which holds a rigid shape but which leaves a depositwhen rubbed against the warm membranes of the nasal cavity. Nasalcompositions can also optionally contain pharmacologically activeingredients e.g., a bronchial muscle relaxant such as amphetamine.

The term labial compositions, as used herein, refers to products which,in the ordinary course of usage are applied to the lips. These includelipsticks, lip pomades and lip creams. These products comprise one ormore oils such as castor oil and mineral oil, one or more waxes such asbeeswax, paraffin, carnauba or ceresin wax and aromatic chemicals forflavor and/ or odor effects. The oil is present in these compositions atlevels between 25% and 65%, the wax is present at levels between 30% and70% and the aromatic chemicals are present at levels between 0.01% and2.0%. The aromatic chemicals can be flavoring oils such as thosementioned hereinbefore for dentifrices or they can be the types morecommonly used in cosmetics such as rose oil, rhodinoyl, methyl ionone orPeru balsam. Optionally coloring materials can also be added to labialcompositions to impart a color to the lips. Suitable coloringingredients are those approved by the US Food and Drug Administrationfor use in cosmetics likely to come into contact with the mouth, such asD&C Red No. 1 and D&C Orange No. 1. When color materials are present,they are used at levels up to about 3% of the finished composition.

The following examples are given solely for the purpose of illustrationand are not to be construed as limitations of this invention, manyvariations of which are possible without departing from the spirit orscope thereof.

EXAMPLE I Toothpaste compositions are prepared according to thefollowing formulas, having menthol present in one and a molar equivalentamount of menthyl keto ester in the other.

Parts by Weight When one brushes the teeth with Formula A he experiencesa minty-Wintergreen flavor and a cooling sensation which remains in themouth for a relatively short time after brushing. When one brushes theteeth with Formula B, a representative oral composition of thisinvention, one experiences a Wintergreen flavor with no minty overtones,and a cooling sensation which persists in the mouth much longer than thecooling sensation imparted by Formula A. Substantially equivalentresults are secured when menthyl pyruvate, menthyl levulinate, menthyl'y-acetyl butyrate or menthyl benzoylacetate are used in Formula B inthe place of menthyl acetoacetate.

EXAMPLE II A mouthwash in accordance with this invention is formulatedas follows:

Parts by wt. Ethyl alcohol (50% in H O) 81.00 'Glycerine 12.00 Saccharin0.30 Flavoring:

-Methyl. salicylate 0.10 Menthyl levulinate 0.15 Sodium coconutmonoglyceride sulfonate 0.6

Water n Balance to This mouthwash, when used in the normal way, providesa Wintergreen flavor with no minty overtones, and a long-lasting coolingsensation in the mouth. Similar results are achieved when the menthyllevulinate of this example is replaced by an equivalent amount ofmenthyl a-ketobutyrate, menthyl a-ketovalerate, menthyl fl-ketovalerate,menthyl-phenylpyruvate, menthyl 'y-ketocaproate, menthyl deltavaleryl-valerate, menthyl epsilon naphthoyl caproate or menthyl zetaphenylacetyl enanthylate.

A mouthwash composition in aerosol form is prepared having the followingingredients:

Parts by wt. Ethyl alcohol 50.00 Glycerine' 4.70 Saccharin 0.30Flavoring:

Methyl salicylate 3.0 Menthyl levulinate L 2.0 Propellant:

Dichlorodifluoromethane 40.0

This mouthwash, in aerosol form, when used in the normal fashion,provides a Wintergreen flavor with no minty overtones, and along-lasting cooling sensation in the mouth.

EXAMPLE IH A chewing gum in accordance with this invention is formulatedas follows:

This chewing gum, when used in the usual manner, imparts to the mouth aWintergreen flavor with no minty overtones, and a long-lasting coolingsensation.

EXAMPLE IV A throat lozenge is formulated in the following manner:

Parts by wt.

Hard candy base 98.70

Cetyl pyridinium chloride 0.30 Flavoring:

Methyl salicylate 0.10

Menthyl acetoacetate 0.90

This throat lozenge, when used in the normal manner, kills bacteria inthe mouth and throat, gives a pleasing Wintergreen flavor with no mintyovertones, and imparts a cooling sensation to the membranes of the mouthand throat which persists for a considerable length of time after thelozenge has been dissolved and ingested.

7 EXAMPLE v Two nose drop compositions are formulated with molarequivalent amounts of menthol and menthyl acetoacetate in the followingmanner:

Parts by Weight Light mineral oil 99 .40 99 .35 Amnhc-tamina 0.50 O.Menthol 0.10 Menthyl acetoacatate 0 Both of these nose dropcompositions, when applied to the nasal passages in the usual manner,relaxthe bronchial muscles and give a pleasing cooling effect to themembranes of said passages. The cooling sensation imparted by Formula B,however, is less intense and more longlasting than that imparted byFormula A.

EXAMPLE VI A lipstick is formulated as follows:

When applied to the lips in the usual manner this composition imparts ared coloration to the lips and gives them a longer lasting, less intensecooling sensation than would be the case if a molar equivalent amount ofmenthol were substituted for the menthyl acetoacetate.

8 {What is claimed is: I r 1. An oral composition comprising from about0.01% to about 2.0% by weight of a menthylketo ester of the formula: i 1y a 0 o I R-iLanmH-ii-O 0H,- -cHi wherein R is alkyl containing from 1to 4 carbon atoms and n is an integer from 0 to 6, and a confection basecarrier.

2. An oral composition in accordance with claim 1 wherein saidconfection base carrier is hard candy.

3. An oral composition in accordance with claim 1 wherein saidconfection base carrier is a cough syrup.

4. An oral composition in accordance with claim 1 wherein the menthylke-to ester is a member selected from the group consisting of menthylpyruvate, menthyl acetoacetate, menthyl levulinate, menthyl a-acetylbutyrate and menthyl benzoylacetate. I

5. An oral composition in accordance with claim 4 wherein said menthylketo ester is menthyl acetoacetate.

References Cited UNITED STATES PATENTS 507,257 6/1939 Great Britain99-140 RICHARD L. HUFF, Primary Examiner US. Cl X.R. 424-31 1 904050UNITED STATES PATENT OFFICE I 569 CERTIFICATE OF CORRECT Patent NO.3,793,463 Dated ebruary 1 v, Invenmflfl) Alfred H-Moelle'r et a1 It iscertified that; error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 2, line 45, change "methanol" to menthol Signed and seeled this2nd day of July l97l (SEAL) Attest: 1

EDWARD M.FLETCHER,JR. C. MARSHALL DANN Commissioner of Patents AttestingOfficer

